Good news! Cancer is history (soon)!
"Endothelial cells – the cells that line blood vessels – grown alongside leukemia cells become corrupted and rescue the cancer cells from many chemotherapy drugs ...
A growing body of evidence suggests that genetic mutations are not enough to cause cancer; tumor cells also need the right environment to grow. ...
About 30% of patients with T-ALL [leukemia] don’t respond to chemotherapy, and some successfully treated patients will have a recurrence years later ...
A growing body of evidence suggests that genetic mutations are not enough to cause cancer; tumor cells also need the right environment to grow. ...
About 30% of patients with T-ALL [leukemia] don’t respond to chemotherapy, and some successfully treated patients will have a recurrence years later ...
build and test a library of 433 drug compounds on the tumor cells alone. They used a high-volume automated platform to test the drugs.
Next, they tested the drugs again on T-ALL cells grown with an endothelial cell line ... They found that these tumor cells were resistant to many chemotherapies, and they became more aggressive. Single-cell RNA sequencing showed changes in gene expression affecting multiple gene pathways in both endothelial and cancer cells grown together. The endothelial cells became corrupted and expressed genes that promote cancer growth. Endothelial cells extracted from T-ALL tumors expressed the same genes, suggesting the model recreates what happens in the body. ..."
From the abstract:
"Key Points
We generated 22 T-ALL PDX models to identify T-ALL liabilities and investigate the interplay between leukaemia and endothelial cells.
We identified active compounds, some of which were effective in-vivo. Interacting EC and T-ALL underwent reciprocal transcriptomic changes.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient-derived tumor-xenografts (PDX) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active compounds with anti-leukemia activity. Since endothelial cells (ECs) can alter drug responses in T-ALL, we developed an endothelial cells (ECs) / T-ALL co-culture system. We found that ECs provide pro-tumorigenic signals and mitigate drug responses to individual T-ALL PDX. ECs broadly rescued several compounds in most of the models, while other drugs were rescued only in individual PDXs suggesting unique crosstalk interactions and/or intrinsic tumor features. Mechanistically, co-cultured T-ALL and ECs underwent bi-directional transcriptomic changes at the single-cell level, highlighting distinct "education signatures". These changes were linked to a bi-directional regulation of multiple pathways in T-ALL and ECs. Remarkably, in-vitro EC-educated T-ALL cells mirrored ex-vivo splenic T-ALL at the single-cell resolution. Lastly, five effective drugs from the two drug screenings were tested in vivo and shown to effectively delay tumor growth/dissemination and prolonging the overall survival (OS). We anticipate that this T-ALL-EC platform can contribute to elucidating leukemia-microenvironment interactions and identify effective compounds and therapeutic vulnerabilities."
No comments:
Post a Comment